(−)-(S)-3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate tartrate of formula I
known under the INN name rivastigmine, is described in CS patent application No. PV 1991-4110 as a substance that induces selective inhibition of acetylcholinesterase activity in the brain. This quality along with good tolerance by the human organism, an option to serve in the form of tablets (oral efficiency) and a long-term effect predestines rivastigmine for treatment of disorders associated with the cholinergic system disorder—especially of Alzheimer's disease.
Racemic 3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate (hereinafter racemic rivastigmine), as a substance with a possible activity against Alzheimer's disease, was described in EP patent 193 926. The method of its production was based on reaction of m-hydroxyphenylethyl-dimethylamine of formula IV
with a carbamoylhalide of formula VI
wherein X represents a leaving group.
Methods for producing these racemic intermediates were described in earlier literature, but no possibility of converting the same into optically active enantiomers is mentioned anywhere.
In the cited CS application PV 1991-4110, it is demonstrated using both “in vitro” and “in vivo” experiments that the optically active (S)-isomer is a much more effective and selective inhibitor of acetylcholinesterase than a racemic mixture of the two isomers.
In the cited application, there is described a method of preparation of rivastigmine from the racemic mixture consisting in preparation of diastereoisomeric salts with (+)-O,O-di-(p-toluyl)-D-tartaric acid and their separation by crystallization. The (S)-enantiomer of rivastigmine was released from the obtained salt with a sodium hydroxide solution.
The basic technological disadvantage of this procedure is that optical resolution is performed only in the final stage of synthesis. This means that at least 50% of the prepared racemic rivastigmine (i.e. the (R)-enantiomer)) represents a useless waste; in fact, this waste is much bigger since optical resolution never separates enantiomers quantitatively. This makes the total yield of the synthesis low and the whole process is economically disadvantageous. Another drawback consists in distribution of the losses into individual steps. In general, the losses in a more advanced intermediate are more cost consuming than those in the initial steps.
As it has turned out in testing said procedure, resolution does not result in achieving satisfactory optical purity and the substance has to be additionally recrystallized (cf. Reference Example 1). The necessity of using the expensive and carcinogenic substance of formula VII (mostly specifically N-ethyl-N-methylcarbamoyl chloride) in an about 300% excess is another drawback.
Resolution in an earlier stage of the synthesis appears, at first sight, as desirable, but far from being feasible. There remains the question whether it is possible to obtain enantiomerically pure intermediates and, especially, whether these products can be used for further synthesis without being subject to racemization. The necessity of recrystallization would cast doubts on advantageousness of such procedure.
It has now turned out that optically resolving the intermediate products (i.e. performing the operation in an earlier stage of production) and performing the final step with an optically active substance, permits to obtain a very good yield of (S)-rivastigmine with retaining high analytic purity.